Compositions and methods for modulating AT2R activity

Abstract

New polypeptide agonists of AT2R are disclosed, as well as pharmaceutical compositions comprising the agonists, methods of their use in the treatment of diseases, conditions or disorders characterized by insufficient AT2R activity or excessive AT1R activity, and methods of their use as laboratory reagents for research purposes.

What is claimed: 
     
       1. A method of activating an angiotensin II Type 2 Receptor (AT2R) protein in a cell expressing the AT2R protein comprising:
 providing to the cell an effective amount of an AT2R agonist comprising the amino acid sequence of the formula:
   A1-A2-A3-A4-A5-A6   (SEQ ID NO: 1)
 
 
 wherein: 
 A1 is Lys; 
 A2 is Pro, 3Hyp or 4Hyp; 
 A3 is Leu or Ile; 
 A4 is Lys; 
 A5 is Pro, 3Hyp or 4Hyp; and 
 A6 is Trp. 
 
     
     
       2. The method of  claim 1  wherein said cell expressing the AT2R protein is in a mammal with a condition characterized by under activation of the AT2R or insufficient activity or insufficient production of a downstream effector of AT2R selected from the group consisting of Mammalian Target Of Rapamycin (MTOR), NHE6, ErbB3, Nitric Oxide Synthase, myeloid leukemia cell differentiation protein (MCL-1) and prostaglandin I2-IP. 
     
     
       3. The method of  claim 2  wherein said condition is selected from the group consisting of diabetes, cancer involving dysfunction of ErbB3, cardiovascular disease, metabolic syndrome, and hypertension. 
     
     
       4. The method of  claim 1  wherein the AT2R agonist is provided by introducing to the cell an mRNA that encodes a peptide of SEQ ID NO: 1, and which is translated in vivo to produce the AT2R agonist. 
     
     
       5. The method of  claim 1  wherein said agonist is used as a reagent to activate the AT2R receptor for laboratory research. 
     
     
       6. The method of  claim 1  wherein the agonist is pegylated for additional stability. 
     
     
       7. The method of  claim 1  wherein the agonist is provided by introducing to the cell a gene sequence encoding a peptide of SEQ ID NO: 1 or an isolated nucleic acid encoding a peptide of SEQ ID NO: 1 via a viral vector which is expressed in vivo to produce the AT2R agonist. 
     
     
       8. The method of  claim 1  wherein said agonist is used as a reagent to stimulate AT2R-mediated activation of D1-like receptors to modulate sodium excretion in a microfluidic simulation system. 
     
     
       9. The method of  claim 1  wherein the method is performed in vivo.